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HS 565 TAKE-HOME MIDTERM EXAMINATION FALL, 2005 RML

I confirm that this midterm examination has been completed without conferring with any of my fellow students or other "experts" in HKLS or related areas. Signature _________Jonathan Durham___________ Student ID Number ___00158-53036 0 __________________ (Please be sure to put your student ID on every page of your exam as well.) Date _______10/11/2005________ DIRECTIONS: Answer the following questions completely following page limits as indicated on each question. Responses should be typed, no smaller than 12 pt font, and double spaced If you use any figures/diagrams, please be sure to provide adequate labeling and/or explanation in order to receive full credit and figures count toward the page limit. Put your student ID number at the top of each page and staple answers together. DUE DATE: October 11th by 5 pm. Hard copy format preferred. However, if you are going to be out of town, you can send it electronically and I will print.

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RESEARCH CONCEPTS (15 pts, limit of one page) 1. a) To test the hypothesis that fasting hyperglycemia and 2-H postchallenge glycemia
independently increase the risk of cardiovascular disease.

b) Subjects were part of the Framingham Study, community based observational

study. This study was a cross-sectional study.

c) Independent variables: Participants were subjects in the Framingham Study;

Subjects had no previous CVD or diabetes; Subjects were missing glucose or Framingham study scores Dependent variables: Age; Gender; FPG levels; 2H FG levels.

d) T-tests, x2 tests, Pearson correlation coefficients and Cox proportional-hazards

regression models.

e)

The prevalence of isolated postchallenge hyperglycemia occurred in 1.9% of women and 1.4% of men and there is only a 7% chance that this occurred because of chance.

2.

For every 0.7 mmol/l increase in FPG there is a 1.088x greater chance of getting a cardiovascular disease. This statistic was analyzed over a period of 4 years in which the levels of PFG were measured in the subjects, and after analyzing the data, researchers found that the levels of FPG was a risk factor for CVD. And for each 0.7 mmol/l increase, you are 1.088x greater chance of suffering from a CVD.

REVIEW OF ENERGY METABOLISM (20 pts, limit of one page)

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1. A) Wilmas walk would be fueled by carbohydrates and fats. Fats would be the main
fuel source for the majority of the walk, while carbohydrates would be the main fuel source at the very beginning of the walk.

b) Aerobic glycolysis by way of the Krebs cycle, ETS and Beta Oxidation. Aerobic
glycolysis would be the energy pathway used, however the Krebs cycle and electron transport chain would fuel aerobic glycolysis for carbohydrates while beta-oxidation would fuel aerobic glycolysis for fats.

c) ATP-CP and anaerobic glycolysis would fuel her sprint at the end of her walk. 2.
Endergonic and exergonic reactions are reactions in which either energy is needed

for a reaction or energy is released. These types of reactions are used in the breakdown of compounds in order to get metabolic pathways started, breakdown ATP to use as E, and also to fuel the metabolic pathways. During metabolic pathways, there is a coupling of the reactions in which endergonic reactions occur because of exergonic reactions and vice versa. In order to get to Beta-Oxidation, triglycerides are broken down into glucose and 3 fatty acid molecules. This reaction requires energy therefore it is an endergonic reaction. There is another endergonic reaction before beta-oxidation when an FFA is combined with CoA: ATP supplies the energy to produce Fatty Acyl-CoA. During BetaOxidation, carbon is broken off of the fatty acid chain and produces 5 ATP per cycle so the overall action is an exergonic reaction because the energy product is bigger than the energy needed, but there are several endergonic reactions that occur during beta oxidation such as FAD and NAD both picking up electrons and protons (H ions) to make FADH2 and NADH+H+.

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LIPID METABOLISM (25 pts, limit of 3 pages)

Once cholesterol is ingested, bile salts emulsify the fats and cholesterol. Once emulsified, the cholesterol is transported to the small intestine (intestinal mucosa) where it re-esterifies with triglycerides in chylomicrons. The chylomicrons, assembled in the intestinal mucosa, transport the triglycerides and cholesterol through the body. While in the plasma, apo CII and apo E are acquired from HDL. In the capillaries of fat and muscle, the triglycerides are removed from the chylomicrons thru hydrolysis. Apo CII and E are then transferred back to HDL. The triglycerides that were removed from the chylomicrons are either oxidized and used as energy in the muscle, or stored for later use in adipose tissue. The chylomicron remnant, now cholesterol rich, is then taken up by the liver. Once in the liver, cholesterol has two possible fates: cholesterol may be secreted into the intestine as bile acids, or it may be packaged into VLDL along with triglycerides and apo B from the liver. VLDL travels to fat and muscle cells where, once again, the triglycerides are removed with help from apo CII and E from HDL, turning the VLDL into IDL. The triglycerides are used in the same manner as the triglycerides from the chylomicron. IDL has two possible fates: bind to the liver or be converted to LDL. To be converted to LDL, the remaining triglycerides are further hydrolyzed by lipoprotein lipase. LDL then transports cholesterol and cholesterol esters to tissue cells, binding to the apo B receptors, for membrane and hormone synthesis, or possibly for storage. HDL is produced in the liver and intestine, and is the source of apo C and apo E. HDL envelops are put into the blood stream to scavenge for cholesterol. HDL picks up cholesterol that has been collected by peripheral tissue cells. CERP, which is activated by apo A, moves cholesterol to the outer lining of the tissue cells for HDL collection. As

ID # 00158-53036 0 HDL collects cholesterol and cholesterol esters, LCAT is also activated by apo A. The activation of LCAT allows cholesterol to transfer to VLDL and IDL. HDL then returns to the liver where cholesterol goes through secretion and degradation via the hepatobilary system and is formed into neutral or acidic sterols. The sterols then service steroid producing organs. Cholesterol goes through complex transportation in the body and has many different roles and possible fates.

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ATHEROGENESIS (20 pts, limit of 3 pages) 1. A) Atherogensis may begin in childhood as fatty streaks in blood vessels. After 30
years the fatty streaks develop into fibrous plaque. After 30-40 years lesions of enlarged plaque become vascularized and calcified. At this point atherogensis may still reversible, however a drastic lifestyle change (medication, diet, physical activity) are required.

b) There are 8 theories on how/why atherogenesis occurs: encrustation; infiltration;

transformation; viral; response to injury theory; hemodynamic theory; monocyte invasion theory; modified LDL theory. Encrustation theory suggests that there is a growth into the intima that starts to shrink the size of the intima. The Infiltration theory is based on fats moving into the artery walls. Transformation theory developed when scientists observed smooth muscle cells where smooth muscle cells should not be located. They also observed that the cells were multiplying, and thought that it was some kind of cancer. At one point there was the viral theory, however no one has been able to prove that a virus causes atherogenesis. The most accepted theory has been the Response to Injury theory. The Response to Injury theory has several stages: the initiating event; platelet aggregation; lipid infiltration. The initiating event is thought to be an injury, especially an injury to the endothelial lining. After the injury occurs platelet aggregation occurs in which PDGF acts on smooth muscle cells and helps the cells migrate towards subendothelial space. The last part of the theory is lipid infiltration which is believed to occur when there is a break in the endothelial lining and lipids are allowed to enter. The injury to the

ID # 00158-53036 0 endothelial lining could occur for several reasons like lack of O2, hypertension, or high blood cholesterol. The hemodynamic theory is based on lateral turbulence in the blood flow for a bulge or lesion. The turbulence doesnt allow epithelial cells to attach to the injured cells and repair the damage. The next theory, Monocyte Invasion theory, explains that monocytes invade the subepithelial lining, and the monocytes become foam cells after gorging on lipids. The last theory is the Modified LDL theory. This theory begins with the idea that LDL penetrates the subendothelial lining, is oxidized, and becomes a chemical attractant to monocytes. The monocytes then penetrate the endothelium and become macrophages. The macrophages then gorge on lipids and lipoproteins and turn into foam cells. The foam cells force the endothelial lining to bulge. At this point in theory, the idea of the response to injury theory comes into play. At the site of the bulge, platelets begin to aggregate and release growth factors that cause smooth muscle cells and fibroblasts to proliferate. A fibrous plaque then begins to form, grow, harden, fissure and fracture. Lastly calcium is deposited at the site of the lesion. Atherogenesis can be treated with drastic lifestyle changes, medication, and through surgical procedures like bypass surgery, balloon angioplasty, and arterial stints.

2. Puddu, Paola, Puddu, Giovanni M., Galetti, Livia, Cravero, Eleonora, and Muscari,
Antonio. (2005). Mitochondrial Dysfunction as an Initiating Event in Atherogenesis: A Plausible Hypothesis. Cardiology 2005; 103: 137-141. Mitochondrial dysfunction as a cause of atherogenesis is the focus in this particular article. The researchers believe that mitochondria dysfunction is a cause of

ID # 00158-53036 0 atherogenesis, and that there are a couple ways in which mitochondrial dysfunction/apoptosis can occur. First, reactive oxygen species (ROS) are produced as byproducts from cell respiration, and mitochondria can be a target of ROS which can damage lipids, enzymes and DNA within the mitochondria. The second cause for mitochondrial dysfunction may be free cholesterol, oxidized LDL, and glycated HDL. Also, another observation that has been made is patients with mitochondrial diseases CVD are common at an early age. It has been observed that oxidative stress plays a role in the development of atherosclerotic cardiovascular diseases, and that the oxidative stress may result in damage to the mitochondria. And the damage to the mitochondria allows for excessive amounts of ROS to target the mitochondria. So, it is a circle that doesnt seem to end because once the mitochondria are dysfunctional increased levels of ROS may occur, which cause oxidative stress, and oxidative stress has been shown to cause mitochondrial damage which allows ROS to attack the mitochondria. The importance of these findings is that if mitochondrial damage is found, then there are several known causes: increase ROS; free cholesterol; oxidized LDL; glycated HDL. Researchers know that the knowledge of the relationship between oxidative stress and atherogenesis is fairly limited. However, with new ideas and studies being published, more and more answers (and questions) are coming. The authors of this article believe the next step is to use genetically engineered cells to learn more about causes and effects of mitochondrial dysfunction. If mitochondrial dysfunction is found to be related to atherogenesis, there could be major steps made towards early detection and treatment of atherosclerotic disease.